Epstein-Barr Virus causes malignant B lymphocyte proliferative diseases in immune deficient humans including most commonly people with HIV infection, organ transplants, or other genetic or acquired cellular immune deficiency states. The focus of this research is to use genetic and biochemical approaches to delineate and define the biological relevance of new molecular and sub-molecular interactions among EBV proteins or between EBV and cellular proteins and thereby develop suitable targets for screening for drugs that would inhibit critical activities of EBV encoded nuclear proteins EBNA-2, -LP, -3A, and -3C in causing EBV infected B lymphocyte proliferations. The overall objectives of this proposal are to discover the molecular and sub-molecular interactions by which EBNA-LP, -2, -3A, and -3C coordinately regulate cell and viral gene expression and cause abnormal B cell growth and to evaluate the biological significance of these potential targets so as to identify those most useful for undertaking screens for inhibitory chemicals. The specific objectives are: l. Recombinant EBV based genetic and biochemical analyses of the role of EBNA-2, -LP, -3A, and -3C in primary B lymphocyte growth transformation so as to better anticipate the effects of inhibition of pathways that are impacted by these viral proteins in causing cell growth and survival. 2. Identify critical sub-molecular interactions required for EBNA-2 and/or EBNA-LP homo- and hetero-association and for interaction with downstream cellular effectors and evaluate the utility of inhibition of these interactions in cell growth and survival. 3. Use recombinant EBV reverse genetic approaches to further define the role of EBNA-3A, -38, and -3C domains in primary B lymphocyte growth transformation. 4. Complete the discovery of the biochemical mechanisms by which the essential domains of EBNA3A, -3B, -3C cooperate with EBNA-2 and EBNA-LP in transcriptional regulation. 5. Identify critical sub-molecular interactions between EBNA-3C and -3A and interactive cellular proteins, including RBP-Jk, PU.l, pl00, and p3OO/CBP, and evaluate the role of these interactions in cell growth and survival. The more basic research aspects of these studies are likely to contribute to the general understanding of lymphocyte transcription and growth regulation.